The Trouble with Big Science

IN THE LATE WINTER of 2013, Eli Broad stopped by the Broad Institute, a nonprofit scientific research center and his namesake. He had just announced that he was increasing his philanthropic gift to $700 million. Those of us working at the Institute that day — I was a data analyst at the time — gathered together on a glass staircase along an overlook, and, all ears, we peered down to the spacious first floor. Eric Lander, founder and director of the Institute, recounted the story of his courtship with Eli Broad, explaining how the benefactor had steadily increased his donations over the years. That day, as a thank you, Lander presented Broad with a collage of thousands of papers published by Institute scientists to show in substantive terms the work that had been completed with his money.

But, by then, a biotech fight had begun to escalate. It had everything to do with a tool the Broad had been developing. In 2011, a couple of years earlier, French microbiologist Emmanuelle Charpentier published seminal work on the CRISPR-Cas9 system, which would soon be developed into a powerful gene-modification tool. Broad scientist Feng Zhang had learned about the system through a Google search, and his lab was one of five independent labs that developed CRISPR-Cas9 into a gene-editing technology by January 2013. Although this five-way tie suggests its development was an inevitable outcome of previous work, not everyone could own the key patents. As a high-profile patent battle for the technology ensued, tens of millions of dollars were funneled from Broad-spinoff Editas Medicine into the tax-exempt nonprofit Broad to fund its legal right to CRISPR-Cas9. Editas now has exclusive rights to the whole shebang for medical applications, which is already paying huge dividends — and includes a chest-thumping $737 million partnership with Juno Therapeutics to use CRISPR to engineer immune system T-cells to seek and destroy cancer cells.

Many scientists, including Charpentier, told me that if the Broad was a step ahead of other scientists, among the first to file an enforceable patent establishing what patent lawyers call “reduction-to-practice,” this was due to its wealth and rapidly deployable biotech apparatus. Cathedral-size industrial campuses like it are thus sprouting up for a reason. Novartis, a Juno competitor and biologics developer, built a new $600 million campus in Cambridge, Massachusetts, on the same block as the $1.4 billion Broad Institute. Such concentrations of power inside science are undoubtedly an ongoing trend, which means we can expect science to be dominated by large scientific hubs positioned to corner resources and patents, and price drugs as high as the market will allow.

On August 30, the Food and Drug Administration approved the first genetically engineered T-cell, an immune cell which is designed to seek and destroy a child’s leukemia. Novartis will sell it in the United States for $475,000, a price nine times the median income in the United States. The price-tag is vexing because general estimates for these biologic medicines cite a manufacturing cost of $25,000. In October, the FDA approved the second genetically engineered T-cell for non-Hodgkin lymphoma, which Kite Pharma will sell for $373,000. These are the first in a new class of biologic medicines that alter our very genes, seeking and destroying all sorts of cancers including solid tumors — and which carry staggering price-tags. This will intensify pressure on our health care system and the national debate on equal access to insurance. Indeed, biotech solutions can be sold on a mythos that a group of improbable scientists with a unique set of talents invented a technology that they should be allowed to sell for as much as possible. Keep in mind, though, that most of these technologies were developed over decades by many academic scientists and paid for by taxpayers. The price of the drug thus reflects a kind of cognitive dissonance — between the collective spirit of publicly funded science and the increasingly brutal fight for control of highly profitable technologies. Entangled in patent fights, Novartis didn’t invent its new drug, but rather, it licensed a piece of the technology from the taxpayer-funded research of University of Pennsylvania scientists, who, as is almost invariably the case, were building on previous work.

Concentrated power in the life sciences is shaping a research community that is far more hierarchical than in the past and driven by investors demanding the most profitable biotech solutions. Large nonprofit centers like the Broad will only accelerate this trend. For instance, Broad-spinout Editas, which has its grip on medical applications for CRISPR in human cells, is entangled in a web of transaction deals, which means the first genetically engineered T-cells created with CRISPR may not cost $475,000 but much more.

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In 1980, the Bayh-Dole Act permitted federally funded research to be patented and transferred to private parties. Soon after, the first biotech patents were upheld, notably for recombinant DNA, which are techniques for splicing and altering genes. CRISPR is now the latest of such techniques. Since then, publicly funded science has shifted to finding drug targets as well as tools that can be spun-out and monetized. This shift to using science to subsidize competitive business interests has consequences. Top-heavy scientific institutions, which have what I call a “quasi-corporate governance,” can provide salaries into the seven figures for managerial scientists and administrators, place company founders into their nonprofit leadership, and hold stock in those companies they start up. The lines can easily be blurred between a science nonprofit and corporate interests. They can also hire strong legal teams and spend lavishly on marketing arms. They are, after all, designed to compete to create products for profit. In short: Their raison d’être is less promoting “public health” than turning rare diseases and cancer into profitable business enterprises — into drugs we subsidize, but which we may not all afford.

Will there be recoil? Science is clearly evolving from its early stages when it depended on taxpayer subsidies to elucidate many basic mechanisms (e.g., sequencing the human genome, and creating roadmaps of epigenetic molecules that bind and regulate DNA), to a new era in which companies begin to fund more of their own basic research. Insofar as this is true, they may, and indeed should, begin to fund more of their enterprise. I have argued in the Boston Globe and STAT that biotech-focused science hubs should ease off of taking public grant money, since these hubs primarily function as business subsidies for generating high-profit drugs and technologies. In retort, Lander and Eric Schmidt, chairman of Google’s parent company Alphabet, wrote an urgent op-ed in the Washington Post titled “Miracle Machine” asking for more public funding, appealing to their own economic interests.

But economics — or the Miracle Machine, if you want to call it that — does not work fairly for everyone, especially in an age when some scientists have the resources to crush their competition and are then able to defend their positions with teams of lawyers. The game is even less fair for consumers hoping to access those drugs. In response to the Lander-Schmidt article, Michael Eisen, a UC Berkeley computational biologist and now US Senate candidate, unleashed a firestorm of incredulous tweets directed at the hypocrisy of elite scientists and investors calling for public funds in such desperate terms. At the same time, he pointed out that researchers and technicians without status have ever-diminishing job security, their jobs typically secure for no more than a year or two.

the #MiracleMachine is fueled by people, and the biggest challenge we face now is that stable careers in basic research are disappearing

Financial competition in the life sciences is being intensified by nonprofit scientific hubs and their industrial partners by means of “free-market philanthropy” or “philanthrocapitalism.” Donating philanthropic money to scientific hubs seems to be a magnanimous act. But it emboldens scientific elites to leverage their newfound wealth to fight for their own business causes, and so for the most profitable drugs. Clearly, these tax-free institutions will be best positioned to win federal grants, since they can claim they have the apparatus and resources to put grants to best use, creating a positive feedback loop in which money flows to the most powerful entities. Venture investors who retain close ties to those institutions will get first dibs on investment opportunities, and it will thus be increasingly important to know the people running these institutions.

Being perched at the top of a big organization will be ever more valued in science as resources are increasingly stockpiled, often under the appeal of “collaboration,” “consolidation of big data,” and, in Napster co-founder and cancer philanthropist Sean Parker’s terms, to “eliminate systemic inefficiencies.” At the same time, scientific hubs will draw on deft salesmanship to enlist the tax-base; indeed, they are already trying to make themselves appealing to a neo-libertarian view — in other words, to an idealistic progressive view that suggests we can ultimately eliminate everything from cancer to schizophrenia.

The neo-libertarian view assumes that people are essentially good — even perfectible — and that “self-anointed” leaders, including those in biotech, should be “unconstrained” by regulation and moral checks because they are ushering us into a world that is more disease-free and equitable for everyone. Under this unconstrained or utopian view, biotech leaders argue that they are brokering a brighter future. But with drugs priced in the high six figures, the dystopian reality is that scientists may be leading us into an ever more unequal future. By contrast, the tragic version of human nature, otherwise known as the “constrained view,” acknowledges that people are guided by innate self-interests and so society requires checks and balances, and constraints. It is the neo-libertarian view that is currently prevailing in the life sciences.

The $3 billion Chan Zuckerberg Initiative is a limited liability company, which allows it to shield managerial salaries while promising to “advance human potential.” The Initiative’s $600 million Biohub, a nonprofit nested at the University of California and Stanford University, aims to fund “risky, sexy science” in a quest to “cure all diseases” while maintaining exclusive rights to commercial patents. The $1.8 billion Cancer Moonshot promises to “end cancer as we know it.” And, while speaking at a Vanity Fair New Establishment Summit called “Hacking Cancer,” Sean Parker said his $250 million Sean Parker Cancer Initiative will make “big bold bets” while maintaining its right to prosecute patents and take proceeds on patents that turn into blockbuster drugs. The Broad Institute has produced videos suggesting we’re on the verge of hacking the brain’s “Black Box,” turning schizophrenia into an engineering problem with a data solution — one it hopes to make money on.

We are thus entering a new era in medicine in which we will see million-dollar gene and cellular biologic medicines. This will include using CRISPR and other gene modification tricks to alter immune cells to fight cancer, and to restore the workings of our own cells and tissues. Scientists have developed the tools to modify our genes to fix diseases such as the brain wasting disease called adrenoleukodystrophy and the rare eye disease called Leber congenital amaurosis. None of this will come cheaply. As Jeffrey Marrazzo, chief executive of Philadelphia-based Spark Therapeutics, which intends to bring the first gene therapy drug to market in the United States for the rare eye disorder, toldThe New York Times, it should be worth a lot to keep your eyesight, and so “[w]e should be compensated for generating that value.” Indeed, many entrepreneurial life scientists see their role as disruptive innovators, not far removed from early computer developers. But there are important differences. Forgoing a high-priced electronic device is not a tragedy, but going without a medical treatment often is. And taxpayers are required to subsidize basic research, so arguably companies have an obligation to ensure access and affordability to consumers. Once the biotech sector begins to take on responsibility for funding its basic research, and is no longer so wholly dependent on the US government to fund the work that feeds into its profitable pipelines, this argument for limiting the power of biotech will become less defensible.

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In 1893, Thomas Henry Huxley wrote in “Evolution and Ethics” that the conflict in acquiring biological resources will define us “as long as the world lasts.” He was fascinated by how social progress and culture emerge as an “artificial world within the cosmos” to check the evolutionary struggle. Cultural forces could be used to promote fairness, or unfairness. Biotech, rapidly becoming ever more sophisticated, may be the most powerful cultural force the world has known — and it looks increasingly unfair. Forms of eugenics, in vitro fertilization, and the transformations of our very genes and cells into profitable biologic medicines for investor-first culture are already being normalized, and inequalities are therefore accelerating. Indeed, the “artificial world” of biotech, rather than an equitable cultivating force in society that promotes access to medicines and health for the poor and disenfranchised, is enhancing the wealth of elite scientists and their lawyers, while making medicine far more expensive and harder to afford.

In his essay “The Virtue of Scientific Thinking” in the Boston Review, Harvard science historian Steven Shapin wrote about how intense competition to survive in the sciences is being further fueled by an investment-culture that turns publicly funded science into an art of self-interested salesmanship, while jeopardizing its virtue. Siddhartha Roy and Marc A. Edwards co-wrote an essay entitled “Science is Broken” in Aeon, in which they describe a climate of “pathological publishing,” driven by insecurity and career anxiety. When a full 76 percent of the academic workforce is composed of adjunct or part-time workers, its members are incentivized to cheat or exaggerate claims. This toxic environment is exacerbated by a top-heavy management culture.

None of this is what we might call a public good, since the jobs for common workers have little security or pay and consumers have to look forward to a new class of gene and cell therapy medicines costing a half-million dollars per treatment, thus compromising their ability to gain fair access to health care. In short, what is happening in the New Gilded Age is happening in science, which is looking less and less like one of the last remaining vestiges of truth and free inquiry. This may be one reason for the rise of citizen science — people are fascinated by science but don’t trust the institutions.

The trouble with big science is essentially that it is a profiteering enterprise. It leverages our worst fears about cancer and other life-threatening diseases to make high-margin profits from biologic medicines. The Broad, Chan Zuckerberg Initiative, and other philanthropic outfits are not the problem per se, but they have the potential to vastly accelerate the problem, contributing to new power imbalances and giving biotech a mandate to pursue the most profitable solutions. Scientists must realize we are living in a time of low institutional trust. And yet science is a public trust insofar as taxpayers fund much of the incremental research that leads to breakthroughs. This trust has never been more in jeopardy.

In a nutshell: taxpayer funding now supports the engines of biotech and it is contributing to inequalities in access to high-priced medicines. It requires checks. But voters have recently turned down initiatives in California and Ohio to cap the costs of medicines. People don’t like the idea of interfering with free markets. But, insofar as science is being monetized, it is, I believe, undergoing a seismic shift: academia is transitioning from an age of primarily basic research of broad public utility into one emphasizing applications and translational medicines. If I am right, then the academic climate of science is disappearing: NIH funding and US government life-support is increasingly a business subsidy benefiting the elite.